A Rare Case When Acromegaly Meets Cushing Syndrome

Abstract Acromegaly is very uncommon, as is non-iatrogenic Cushing syndrome; we discuss a patient who was found to have both a pituitary adenoma causing acromegaly and a cortisol-producing adrenal adenoma causing Cushing syndrome within 1 year. She was a healthy, 44-year-old woman who presented with visual changes and was found to have bitemporal hemianopsia and a 3.3-cm pituitary mass along with central hypogonadism, central hypothyroidism, and suppressed adrenocorticotropin and discrepant cortisol. After transsphenoidal resection she had declining, but persistently elevated, insulin-like growth factor 1 (IGF-1), raising concern for persistent acromegaly. She also was experiencing several cushingoid symptoms and was found to have elevated salivary and urinary cortisol. An abdominal computed tomography scan showed a 3.1-cm adrenal adenoma, and she subsequently underwent adrenalectomy. Following adrenalectomy, her cortisol levels normalized, and her IGF-1, growth hormone, and oral glucose tolerance test showed substantial improvement consistent with previous reports linking hypercortisolism and elevated IGF-1 levels. Combinations of pituitary and adrenal disease are seen in a handful of genetic syndromes; however, her clinical presentation and genetics do not fit with known syndromes. This case describes two rare endocrine tumors in one patient and associated limitations of routine laboratory testing.


Introduction
Acromegaly resulting from a pituitary adenoma is a very uncommon occurrence, with roughly 30 to 70 individuals affected per million people [1].Cushing syndrome from an adrenal adenoma is even rarer, with approximately 0.6 individuals affected per million people [2].Based on these statistics, the chances of both co-occurring in an individual patient would be astronomically low; however, several genetic syndromes can link these 2 diseases, including multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 4, Carney complex, and McCune-Albright syndrome.
In addition to the challenge of diagnosing both conditions simultaneously, the presence of both causes a laboratory dilemma.Biochemical control following treatment of a somatotroph adenoma is characterized by growth hormone (GH) suppression during an oral glucose tolerance test (OGTT) and normalization of age-adjusted insulin-like growth factor 1 (IGF-1) levels [3].There is limited information on how hypercortisolism affects these tests, but there are some study data that suggest patients with Cushing syndrome have elevated IGF-1 compared to controls [4,5].Patients with multiorgan endocrine involvement need to be monitored for confounders in laboratory testing.

Case Presentation
A 44-year-old woman presented to her optometrist for progressive blurring of vision and was found to have bitemporal hemianopsia.Her medical history consisted of only mild hypertension for which she was not taking any medications.She reported no contributory family history.A pituitary magnetic resonance imaging scan was obtained showing a 2.1 × 2.5 × 3.3-cm macroadenoma with invasion into the right cavernous sinus, and with upward displacement and flattening of the optic chiasm (Fig. 1).
She had significant elevation of IGF-1 to 610 ng/mL (79.7 nmol/L) (49-240 ng/mL; 12.3-31.4nmol/L), with an elevated GH level of 23 ng/mL (23 μg/L) (0.01-3.61 ng/mL; 0.01-3.61μg/L) consistent with acromegaly.She also had coexisting pituitary deficiencies including hypogonadotropic hypogonadism and central hypothyroidism (Table 1, column 2).Morning adrenocorticotropin (ACTH) was low at less than 5.0 pg/mL (<1.1 pmol/L) (7.2-63 pg/mL; 1.6-13.9pmol/L) on multiple occasions with morning cortisol within normal limits at 18 μg/dL (497 nmol/L) (4-23 μg/dL; 111-1630 nmol/L).When the patient was seen by endocrinology she confirmed several symptoms and signs consistent with acromegaly including amenorrhea, arthralgias, skin tags, coarsening facial features, increased teeth spacing, hair thinning, increased ring and shoe size, hair loss, and new prediabetes.She also reported a 30-pound weight gain, but lost most of this weight by following an intensive weight-loss program consisting of a restrictive diet.Her menstrual periods ceased only 2 months prior to presentation.She associated most of her symptoms to changes in her routine and stressors during the COVID-19 pandemic and did not seek medical evaluation early for these symptoms.Due to uncertainty regarding her low ACTH level in conjunction with normal cortisol levels, she was started on perioperative glucocorticoids as well as thyroid replacement.She underwent a transsphenoidal resection of her pituitary macroadenoma, and the surgical pathology revealed a sparsely granulated somatotroph adenoma that was PIT1 positive, GH weakly positive, keratin cAM 5.2 positive, Ki67 index 1.2%, and was negative for prolactin, ACTH, and TPIT.She had repeat laboratory tests after a hydrocortisone taper was completed (see Table 1, column 3).Her IGF-1 had improved to 385 ng/mL (50.3 nmol/L) (49-240 ng/mL; 12.3-31.4nmol/L) but it was still elevated, her gonadotropins were still undetectable, and her ACTH was still suppressed with normal morning cortisol levels.She also had a robust response on an ACTH stimulation test.A 3-month postoperative pituitary magnetic resonance imaging scan showed a lobular, hypoenhancing soft tissue in the dorsal aspect of the sella concerning for possible residual tumor.By this time, her most   A computerized tomography scan of the abdomen was obtained showing a 3.1-cm, lipid-rich left adrenal adenoma (5 Hounsfield units), which confirmed the likely source of her coexisting adrenal Cushing syndrome (Fig. 2).

Treatment
The patient underwent laparoscopic left adrenalectomy with pathology consistent with adrenal adenoma.

Outcome and Follow-up
In the following weeks after surgery, the patient reported considerable symptomatic improvement including better sleep, improved ankle swelling, and weight loss.To our astonishment, follow-up laboratory tests in the following months showed recovery of the hypothalamic-pituitary-gonadal axis (see Table 1, column 4), with return of menses, and improvement in the IGF-1 level to normal levels, and successful suppression of GH level on a 2-hour OGTT: 0.88 ng/mL to 0.20 ng/mL (0.88 μg/L to 0.20 μg/L).This was consistent with biochemical remission of acromegaly (see Table 2).
Despite hydrocortisone wean attempts, the patient's hypothalamic-pituitary-adrenal axis has not recovered fully to date.However, there is promising early detection of the ACTH level, which is no longer suppressed.The patient did undergo genetic testing and is heterozygous for a variant of unknown significance detected in the PTCH1 gene, which has no established connection to the development of acromegaly or adrenal Cushing syndrome.

Discussion
The definition of biochemical control of acromegaly after resection has been redefined over time [6].Broadly, it is defined as GH suppression during an OGTT and normalization of age-adjusted IGF-1 level 3 to 6 months postoperatively [6,7].However, it has been estimated that up to 30% of patients could have discrepant results between IGF-1 and GH levels.Suppression was traditionally defined as GH nadir of less than 1.0 ng/mL (<1.0 μg/L) after OGTT, but now with ultrasensitive assays, the consensus for suppression is a GH level of less than 0.4 ng/mL (<0.04 μg/L) [6].There was also a retrospective study of postsurgical patients with a mean follow-up of 39 months that suggests a 3-month IGF-1 level less than 1.25 times the upper limit of normal is associated with long-term remission [3].There are also other factors that can affect GH and IGF-1 levels, such as pregnancy, diabetes, oral estrogen (not transdermal estrogen), and critical illness [7].There is limited literature on the effects of hypercortisolism on IGF-1 levels, but higher IGF-1 levels were identified in patients with Cushing syndrome as early as 1993 [4].There was also a retrospective case-control study, published in 2019, measuring preoperative and postoperative IGF-1 levels in Cushing disease patients to matched controls that found a significantly higher proportion of Cushing patients with elevated serum IGF-1 above the reference range compared to controls [5].In addition, among the patients who achieved remission of their Cushing, IGF-1 levels decreased significantly postoperatively.Though this study did not involve acromegaly patients and included patients with pituitary Cushing disease rather than adrenal Cushing syndrome, we observed in our case a similar phenomenon by which the IGF-1 normalized after cure of the overt hypercortisolism.This is a rare case, but similar cases have been reported, the most similar of which was published in 2011 and detailed the presentation of a patient with acromegaly who was found to have hypercortisolism from an adrenal adenoma 6 years after the resection of her pituitary adenoma.The authors reported that, post adrenalectomy, the patient needed significantly less pegvisomant for biochemical control of her acromegaly [8].
Our case is different in that our patient had overt Cushing syndrome, whereas this patient had mild autonomous cortisol secretion.Because of suppressed ACTH and the focus on GH excess in association with a macroadenoma, we did not initially look for cortisol excess as a cause of our patient's symptoms.Also, because most visits were conducted by televideo during this time, and there were still COVID restrictions and more limited access in the health care setting, not all clinical features were immediately evident, and in addition, the overlap of symptoms for these 2 different conditions made the diagnosis challenging.
During our patient's workup, genetic testing was completed to identify a unifying genetic syndrome explaining the cooccurrence of 2 different endocrine tumors.Here genes were analyzed using next-generation sequencing and Sanger sequencing.During analysis, the coding domains and a portion of flanking regions were searched; notably, the promotor genes and a portion of the untranslated regions were not reported.The only remarkable finding in her genes was PTCH1, a variant of unknown significance that has no reported relationships to acromegaly or Cushing syndrome.The known syndrome that overlaps the most with her disease would be MEN1 syndrome.Most defects in the MEN1 gene would have been caught with this approach to analysis; however, a portion of the promoter and untranslated genes was not reported.Genes in these regions may be responsible for 5% to 25% of MEN1 gene dysfunction [9].However, she had no evidence of primary hyperparathyroidism, which has a high penetrance in MEN1 and is most often the first presentation in MEN1 (>93% penetrance and first manifestation in >67%) [10].Carney complex is another disease process that could be considered, but our patient did not have primary pigmented nodular adrenocortical disease.McCune-Albright syndrome is unlikely given that she had no fibrous dysplasia of bone or café au lait skin macules on examination.
This case raises the question of whether we should be actively searching for additional endocrine abnormalities in patients diagnosed with one endocrine problem.We believe that actively searching for other endocrine abnormalities should be

Figure 1 .
Figure 1.Initial magnetic resonance imaging scan of the pituitary showing a large 2.1 × 2.5 × 3.3-cm macroadenoma with invasion into the right cavernous sinus and with upward displacement and flattening of the optic chiasm.A, Sagittal view.B, Coronal view.

Table 1 .
Pituitary laboratory values before intervention, 6 weeks after pituitary resection, and 4 weeks after adrenalectomy (6 months after pituitary resection)